Only approximately 1/3 of fertilized ova result in a successful pregnancy. Genetic variability in either the mother, the embryo, or both likely contribute to embryonic and fetal loss. However, identifying specific genes that influence human fertility is challenging. We have been conducting prospective studies of the effects of human leukocyte antigen (HLA) genes on pregnancy outcome for over 15 years in the Hutterites, a religious isolate of European descent. Our studies have taken advantage of the extensive characterization of genes in the HLA region and the detailed prospective reproductive data available for this population. We continue to see increased miscarriage rates among couples matching for HLA-B alleles and decreased fecundity (measured as the length of the interval to pregnancy) among couples matching for HLA-DRB1 alleles. Furthermore, we have characterized variation in the 1.1 KB upstream region of HLA-G, including all of its known regulatory elements, and demonstrate an association between a promoter region polymorphism and fetal loss in the Hutterites. We also present evidence for a locus on chromosome 6q24.3 that influences fecundity in the Hutterites. In this application, we propose to characterize the variation in the HLA-G promoter region that is associated with fetal loss with respect to its effect on transcription, to positionally-clone the gene on 6q24.3 that influences fecundity, and to replicate these studies in out bred couples with recurrent miscarriage and infertility. We propose that the clinical and genetic homogeneity in the Hutterties make them ideally suited for identifying genes that influence complex phenotypes, such as fecundity and fetal loss. These studies may reveal novel mechanisms underlying infertility or pregnancy loss in out bred couples, and perhaps suggest new therapeutic strategies.